Copyright © 2013 by
Archives of Razi Institute, Vol. 68, No. 2, December (2013) 91-99
Razi Vaccine & Serum Research Institute
DOI: 10.7508/ari.2013.02.001
Review Article
Hemiscorpius lepturus envenomation: Manifestations and
management with specific antivenom
Zare Mirakabadi, A.
Department of Venomous Animal & Antivenom Production, Razi Vaccine & Serum Research Institute,
Karaj, Iran
Received 20 Oct 2012; accepted 05 May 2013
ABSTRACT
Scorpionism is a known significant problem of medical and social importance in many tropical and
subtropical regions including the Middle East. In Iran, highest prevalence of scorpion sting about 60%
of all the stings has been reported from Khuzestan province. Among the 21,000 cases of reported
scorpion stung patients, 12% were caused by H. lepturus, but contributed to 95% of all moralities in
scorpion stung patients. The sting of H. lepturus does not produce an immediate pain as does the sting
of other scorpions, rather cause delayed swelling that may diffuse and is often accompanied by late
necrosis at the sting site suggestive of less significant role of the nervous system stimulation. Since the
venom from H. lepturus is cytotoxic in nature and the renal response and blood toxicity are normally
simultaneously manifested, it is suggested that the toxin binds to kidney tissue and potentially induce
acute renal failure in stung patients. Pharmacokinetic analysis revealed that Intramuscular (i.m)
injection of antivenoms is ineffective in neutralizing the action of venoms. Although some reports
mention the slow distribution rate of H. lepturus venom following sting, but since the cytotoxic effect
of venom from this scorpion is irreversible by antivenom once it occurs, it is recommended to use
antivenom through intravascular (i.v) route. Antivenoms of F(ab)2 fraction are the best choice of
treatment for their fast extravasation, their ample distribution into the extracellular space, and their
prolonged retention time.
Keywords: Hemiscorpius lepturus,antivenom, manifestations, management
INTRODUCTION 
Scorpionism is a known significant problem of
medical and social importance in many tropical and
subtropical regions including the Middle East (Balozet
1971, Farghly and Ali, 1999, Silva et al 2000,
Dehghani et al 2009). In Iran, highest prevalence of
Author for correspondence.Email: [email protected]
*
scorpion sting about 60% of all the stings has been
reported from Khuzestan province. The highest rates of
annual incidence of scorpion sting per hundred
thousand populations are reported to be 1563 in
Khuzestan, 1290 in Kohkiloye Boyerahmad and 826 in
Ilam, provinces of Iran (Azhang & Moghisi 2006). At
least 7 important scorpion species are found in
Khuzestan with varied prevalence of Androctonus
crassicauda with 28.7%, Hemiscorpius lepturus with
92
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24.9%, Mesobuthus eupeus with 21.7%, Compsobuthus
matthiesseni with 20.6%, Hottentotta saulcyi with
3.35%, Orthochirus scrobiculosus with 0.5 % and
Hottentotta schach with 0.5% (Pipelzadeh et al 2007).
Among the 21,000 cases of reported scorpion stung
patients in1996, 12% were caused by H. lepturus and it
contributes to 95% of all moralities in scorpion stung
patients (Radmanesh 1990). It is interested to know that
the average venom content in telson of scorpion (H.
lepturus) is only 250μg and the LD50 of H. lepturus
venom in mice is 126μg/mice that shows the toxicity of
this venom is much less than the other scorpions venom
like O. dorea with LD50 of 8 μg per mice (Jalali et al
2010), but however the mortality rate in H. lepturus
scorpion stung patients is higher as compared to others
(Jalali et al 2010). Adiguzel et al in the year 2007
reported that over 39% of the stings were in children
aged up to 10 years, while those aged 60 and over
constituted only 3.2% of the reported accidents,
suggesting that the risk of suffering accidents
diminishes with age. They attributed the high incidence
of stings among children to the higher inquisitive
nature, risk-taking behavior such as lifting up stones
and putting on clothes and shoes without checking
them for the presence of scorpions (Adiguzel et al
2007). The body extremities accounted for almost 67%
of the site stings, a frequency that is not very different
from other studies that invariably have shown that the
afflicted body parts are mostly the extremities (hand,
leg, foot, arm) (Farghly & Ali 1999, Silva et al 2000).
These findings may be explained on the basis that the
exposed limbs are usually used in most manual
activities and moving makes the scorpion retreat and so
stings occur in other parts of the body, such as neck and
head, when resting or sleeping.
Venom of Hemiscorpius lepturus. The electrophoretic
profiles, with 15% acrylamide gel, of H. lepturus
venom showed at least 10 different protein
components, which were widely distributed in the
range of molecular mass between 3.5 kDa and 260
kDa. There were several major bands, being located at
the approximate molecular weights of 4 kDa, 30 kDa
and 50 kDa (Ramin et al 2010). The venom of H.
lepturus showed significant amounts of enzymatic
activities against casein; gelatin, or hyaluronic acid by
zympgraphy method. This venom presented a weak
caseinolytic band around 30 kDa, which appears to be a
metalloproteinase. Gelatinolytic activity was similarly
observed in this venom; with one weak band placed
around 30 kDa, and a stronger band near 50 kDa. In
addition, hyaluronidase activity was detected at around
40 kDa (Ramin et al 2010). In fact, identification of a
novel compound named Hemicalcin, a neurotoxin
which opens ryanodine-sensitive Ca2+ channels similar
but significantly more toxic than maurocalcine in the
venom of H. lepturus has been reported previously
(Shahbazzadeh et al 2007). In a study by our group of
research workers we found that one ml of polyvalent
snake antivenom, produced by Razi Research Institute
is able to neutralize H. lepturus venom equivalent to 5
LD50 in mice (Unpublished data). It was very
interesting, since almost all research workers are sure
that snake antivenom is unable to neutralize the venom
of scorpion. We believe that this is due to the similarity
in enzymatic constitute of venom of scorpion H.
lepturus and snake venom. However Ramin et al 2010
believe that, these enzymatic entities are quite similar
by their molecular weights to those of Loxosceles
desserta.
Local signs and symptoms. The local signs produced
in rabbits by the venom of H. lepturus included red
circle and inflammation at the site of injection
especially when the injection dose of venom increased
to above 500μg/kg (Zare et al 2007). It has been
reported that subcutaneous injection of the three doses
(0.01, 0.1 & 1LD50) of venom produce some changes
in skin structures with clear cell aggregation in
epidermal and collagen precipitation in dermal layers.
A marked dermal layer discontinuity, atrophy in
subcutaneous layers with severe hemorrhage observed
in envenomed rats (Ajj 2003). The appearance of red
circle and inflammation without serious pain around
the injection site which appeared as local sign is likely
due to the necrotizing property of the venom that may
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cause damage to the presynaptic sensory nerves leading
to localized anesthetic effects and/or to the inhibitory
effects on the release of neurotransmitters (Piplezadeh
et al 2007, Jalali et al 2010). It is also suspected that
the proteases of H. lepturus venom may play an
indirect role in the activation of complement system,
which participates in dermonecrosis of the envenomed
patients as observed in Loxocelism (Espino-Solis et al,
2009). The sting of H. lepturus does not produce an
immediate pain as does the sting of other scorpions,
and generally give rise to delayed swelling that may
diffuse and is often accompanied by late necrosis at the
sting site suggestive of less significant role of the
nervous system stimulation or to be due to the
damaging action on the nerve fibers that transmit the
pain signals (Afzali & Pezashki 1998, Radmanesh
1990). The local necrosis and various skin responses
that develop following H. lepturus sting may last from
a few days to several months. This phenomenon was
attributed to the small size of the sting, which is
approximately 1mm in length, and to the possibility of
delay in absorption from the sting site (Radmanesh
1998). When a patient stung by H. lepturus, the type of
cutaneous reactions, at early stages of presentation,
usually correlated with the severity of intoxication.
However, this classification is not absolute, since
systemic effects can develop without extensive local
reactions. When the patients are stung at high local
blood flow areas such as face, trunk, neck or proximal
extremities, systemic effects can develop without
extensive local reactions. Therefore, it is likely that the
direct correlation of cutaneous manifestations with
eventual development of systemic is not absolute
(Radmanesh 1998).
Systemic signs and symptoms. Clinical picture
observed among the stung patients by H. lepturus
suggests both local and systemic effects with the
presence of several clinical syndromes and varying
intensities that dominate the clinical presentation and so
varied and complicated compared with other scorpion
stings manifestations. Complications that were reported
for human victims stung by H. lepturus scorpion
93
include severe fatal haemolysis, renal failure, ankylosis
of the joints, psychological problems and
cardiovascular complications (Radmanesh 1990).
Blood toxicity and renal failure have higher probability
in children younger than 10 years old. The reason
underlying the severity of symptoms of envenoming in
children could be related to their smaller body mass and
decreased physiological reserves compared to adults,
making them vulnerable to developing the most
common signs and symptoms of systemic symptoms,
particularly renal failure. Since the venom from H.
lepturus is cytotoxic in nature (Radmanesh 1998,
Pipelzadeh et al 2006) and the renal response and blood
toxicity are normally simultaneously manifested, it is
reasonable to suggest that the toxin binding to kidney
tissue may potentially induce acute renal failure in
patients following severe scorpion accidents presented,
such as decreased urinary volume, hemoglobinuria,
proteinuria and lower creatinine excretion (Pipelzadeh
et al 2006). However, a contribution from the release of
endogenous neurotransmitters and other inflammatory
mediators cannot be excluded. The high incidence of
blood toxicity and renal involvement observed in
patients stung by H. Lepturus had not been reported in
the clinical picture following other scorpion stings. The
data from percentage of incidences of various clinical
signs and symptoms in relation to the presence or
absence of renal toxicity, and hence degree of toxicity,
showed that most of these symptoms were observed
when there was a concurrent presence of renal
involvement. Although most of scorpions from
buthidae family cause significant myocardial infarction
in heart (Hering et al 1993, Kilger et al 2000), in
experimental animals studies on rabbits H. lepturus
venom did not effect the heart seriously and it seems
that the appearance of signs and symptoms related to
the neurotransmitters release is not observable and the
symptoms related to cytotoxic nature of this venom is
more prominent (Zare Mirakabadi et al 2010).
However, high dose (3000μg/kg) of H. lepturus venom
in rabbits caused mild ST elevation and sinus
bradycardia in limb lead II. The subcutaneous injection
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of 6500μg/kg (LD 50) of H. lepturus venom in rabbits
caused the signs and symptoms similar to the signs and
symptoms reported for the envenomation by the venom
of scorpions from buthidea family (Zare et al 2006,
Jalali et al 2010). It seems the signs and symptoms
appears in case of acute envenomation by H. lepturus
is due to the neurotoxin in the venom of this scorpion
species ( zare Mirakabadi et al 2010). Identification of
Hemicalcin, a neurotoxin which opens ryanodinesensitive Ca2+ channels similar but significantly more
toxic than maurocalcine in the venom of H. lepturus
has been reported which can explain the neurological
disturbances in patients specially children stung by this
scorpion (Shahbazzadeh et al 2007). In the same
study, a rise in the CK-MB and CPK in animals
following
H. lepturus venom injection at 3 hours
following venom injection my be indicators for the
delayed type of damage to the heart. It is reported that
approximately 30 to 50 percent of dialysis patients
without evidence of myocardial injury exhibit an
elevation in the CK-MB fraction (McLaurin et al 1997,
Green et al 1986). A marked rise in BUN, urea,
creatinine, ALT and AST were observed especially at 3
hours after venom injection (Zare et al 2006). The
elevated levels in these parameters are indicative of
damage to the kidney and liver. When RBCs were
exposed in vitro to various concentrations of H.
lepturus venom, there was a highly significant
(p<0.001) increase in osmotic fragility. This is an
indicator of the venom direct action on RBCs. In vivo
studies also confirm these results which may be due to
the presence of an enzyme, like phospholipase A2, in
the venom of H. lepturus. This phenomena may be the
cause of hematuria in patients stung by this scorpion
species(Zare et al 2006). The hyaluronidase of this
scorpion venom may affect the stability of blood vessel
walls (Veiga et al 2001) and increase the spreading of
venom toxins. Systemic disturbances, such as renal
failure, hemolysis and other clinical manifestations, in
the envenomed patients by this scorpion may be
attributable to the enzymatic components (Ramin et al
2010).
Pharmacokinetics of scorpion venom. pharmacokinetical
studies of scorpion venom were performed either by
measuring the plasma level of 125I-labeled venom
(Ismail et al 1974, 1983, 1380, Calderon- Aranda et al
1999) or by following toxin concentrations by ELISA
(Revelo et al 1996, Santana et al, 1996, Krifi et al
2001). The result of the pharmacokinetic analysis,
performed on the venom of scorpions from buthidea
family revealed that the time to reach the maximal
venom concentration in the blood, Tmax, was virtually
brief (about 2 hr) and the apparent terminal half-life
was 496 min. The pharmacokinetics of the venom
showed that after a rapid ascending phase, which
means a fast absorption of scorpion toxins, the toxin
concentrations in plasma reached a maximal value (C
max) after T max of 120 min. Then the curve followed
a rather slow bi-phasic decline, followed by a slow and
a more slowly declining phase (Ismail et al 1998). In
another study biodistribution studies were carried out in
Wistar rats at different time intervals after IV
administration of the labeled venom from scorpion of
buthidea family. Within 5 min of administration, the
labeled venom was found in the blood (27%), muscle
(30%), bone (13%), kidney (12%), liver (10%), and
other organs. The level of venom in the kidneys was
higher than in the liver. The labeled venom was
excreted through renal and hepatobiliary pathways
(Murugrnsan et al 1999). Hence it is clear that the
venom distribution in scorpion stung patients in
extravascular compartment is fast, explaining the early
appearance of the symptoms. After subcutaneous
injection in rabbit, 70% of the venom is detected in the
blood circulation in less than 15 min, and the maximum
serum concentration is reached in less than 2 h (Devaux
et al 2004). The accumulation of toxins in some
internal organs is associated with direct tissue effects.
The concentration of venom in the kidneys not only
depends on the renal excretion but also on a specific
phenomenon of concentration (Abdel-Haleem et al
2006), which induces functional effects due to the
reduction of local flow of the blood (De Sousa et al
2005). When the radiolabelled H. Lepturus venom was
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injected subcutaneously to rats, the time to reach the
maximal venom concentration in the blood, Tmax, was
about 2hr and the apparent terminal half-life was
103min. This report showed slow absorption and
gradual distribution from blood into tissue and slow
removing of H. Lepturus venom. So it is likely that the
release of venom from the site of injection was gradual
(Jalali et al 2012). The main reason was attributed to
large molecular size of active proteins in the venom of
H. lepturus. Recently our group examined the
biodistribution of the venom of H. Lepturus injected by
intravascular rout in rats and found that at 4 hours
following venom injection more than 80% of the
venom is accumulated in the kidney and bladder
(unpublished data).
Specific Antivenom. According to (Touloun et al
2001), about 40% of the scorpion stings were treated
exclusively with traditional medicine in Morocco, 27%
by both the traditional and modern medicines, 28% by
modern medicine alone and 7% remained without
treatment. The role of antivenom in the treatment of
scorpion stings remains controversial and the
effectiveness of antivenom treatment depends on the
potency of the antivenom (Hisham, 1997, Isbister et al
2003, Hammoudi-Triki et al 2004). Different
approaches to the treatment of scorpion envenoming
have been advocated by different investigators. Some
investigators recommend treatment of mild cases of
envenoming with symptomatic measures and/or
antivenin and severe cases with symptomatic measures,
support of vital functions and i.v. injection of antivenin
[Freire-Maia and Campos 1987, Freire-Maia and
Campos 1989]. Others recommend close monitoring
in ICU for pulmonary or CNS complications, especially
for children ( Gueron et al 1992). The crucial factors in
the success of serotherapy can be the potency of the
antivenom and its dose and route of administration. The
common remedy of the patients envenomed by H.
lepturus is the intramuscular or intraventricular
injection antivenom to neutralize the undesirable
venom effects and other symptomatic treatments (Jalali
et al 2010). It is important to note that it results in a
95
delayed neutralization of toxins that is 10-fold lower
efficacy compared to the intravenous route ( Ismail and
Abd-Elsalam 1998). Ismail and Abd-Elsalam
concluded the i.m injection of antivenoms is certainly
ineffective in neutralizing the action of venoms, as the
venoms and antivenom have no opportunity to meet
quickly enough in the central or tissue compartments.
Ismail and his co-investigators showed that low doses
of antivenom are unable to neutralize completely the
electrocardiographic effects of the venom in
experimental animals and the ineffectiveness of
antivenom in preventing or abolishing cardiovascular
manifestations of scorpion envenoming had been
ascribed to the low titers of commercial antivenoms
used (Ismail 1993, Ismail 1995, Ismail and AbdElsalam 1988, Ismail et al 1993). The i.m injection of
antivenom is also reported to be useless in the treatment
of scorpion envenoming because of the slow absorption
and distribution of the immunoglobulins compared with
the rapid absorption and distribution of scorpion
venom. (Mohammad 2003). In contrast to all the
reports indicating inefficacy of intramuscular injection
of antivenom in neutralizing the scorpion venom in
central compartment of stung patients, a report by Jalali
et al 2012 considering Tmax value of H. lepturus
venom and polyvalent F (ab) 2 antivenom in rats and
the results indicate that venom absorption is
comparatively slower than antivenom and the maximal
concentration of venom reached 1.5hr after antivenom.
Hence the research workers mentioned that
intramuscular injection route of antivenom would be
useful, only if administered in referrals under 2hr
following H. Lepturus sting (Jalali et al 2012). It is
needed to clarify that unlike the scorpions from
buthidae family which the cause of manifestation in
human is due to the neurotoxins with molecular weight
about 7KD (Ismail et al 1974, 1980, 1983), most of the
manifestations caused by scorpion, H. lepturus is due to
the cytotoxic components of molecular weight about 30
KD in the venom (Ramin et al 2010). The medium
molecular size of cytotoxins in the venom of
H.Lepturus can be the reason for efficacy of antivenom
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against H.Lepturus when injected intramuscularly
within two hours following scorpion sting (Jalali et al
2012). However since the cytotoxic effect of venom is
proved to be irreversible by antivenom if once it occurs
(Zare et al 2011, Hering et al 1993), it is recommended
to inject the antivenom by i.v rout if any systemic
signs and symptoms are seen in stung patients. The
time of antivenom injection has important role in
effectiveness of antivenom. When antivenom is
injected at early time following scorpion sting the
chance to prevent the appearance and progress in
systemic signs and symptoms increases significantly.
Antivenom injection time related effects of
Hemiscorpius lepturus in rabbits studied by our group.
It was found that although the antivenom at 1 hrs
following venom injection was unable to reverses the
biochemical changes occurred following venom
injection but, the acute rise in the various parameters
stopped following antivenom administration (Zare et al
2011). This indicated that the antivenom is able to
neutralize the circulating venom and prevent further
disruption of tissues by the venom. In next group of
animals which received the antivenom 3 hours
following venom injection the rise continued even after
24 hours in most of parameters which indicate that the
disruption of tissues by the venom is not able to be
reversed, once it occurs (Hering et al 1993, Zare et al
2011). Antivenom binds to and neutralizes the venom,
halting further damage, but do not reverse damage
already done. (Gueron et al 1993). Some scorpion
stings which were previously inevitably fatal have
become only rarely fatal provided that the antivenom is
administered soon enough (Pipelzadeha et al 2006).
Pharmacokinetics of the antivenom. It is recognized
that antivenom should contain suitable pharmacokinetic
parameters and be distributed rapidly to the tissues to
neutralize distributed toxins. The choice of preparing
specific IgG or fragments appears to depend on the size
and toxicokinetics of the principal toxin(s) of the
venoms. Large relative molecular mass (Mr) bivalent
antibodies (IgG and F(ab)2 fragments) may be effective
for the complete and prolonged neutralization of
intravascular toxins (e.g. procoagulant enzymes) which
have a long half-life in envenomed patients, whereas
low Mr and monovalent IgG fragments such as Fab
may be more appropriate against low-molecular-mass
neurotoxins which are rapidly distributed to their tissue
targets and are rapidly eliminated from the patient’s
body (Gutiérrez et al 2003 ). The time course of
antivenom concentration in plasma, determined by
radioactivity measurements, showed a bi-exponential
decline, indicating that the antivenom was distributed
into two compartments with a terminal half-life of
496.43 min. Extravasation of IgG antivenom is likely to
occur via convection, i.e., movement of IgG with fluid
flow from blood to tissue through paracellular routes,
or following an endocytic route in endothelial cells
(Lobo et al 2004). The elimination half-life of IgG
antivenom was reported to be 82 hrs in experimental
rabbits. These values, together with those of clearance
and mean residence time, point to a prolonged presence
of IgG antivenom in the body. A relatively prolonged
elimination half-life has been also described for IgG
and F (ab)2 antivenoms by other workers. (Ismail et al
1998, Pe´pin-Covata et al 1996, Rivie`re et al 1997). A
wealth of literature indicates that IgG, F(ab)2 and F(ab)
antibodies are equivalent in their efficacies to neutralize
their antigens. Yet F (ab)2 antivenoms are the best
choice treatment for their fast extravasation, their
ample distribution into the extracellular space, and their
prolonged mean retention time (MRT) (Va´zqueza et al
2005).
Antivenom Impurities. The presence of impurities
in antivenom increases the possibility of anaphylactic
shock characterized by several actions including
increased vascular permeability, vasodilatation,
bronchial and visceral smooth-muscle contraction,
mucous
secretion
and
local
inflammation
hypersensitivity reaction characterized by edema in
several tissues and drop in blood pressure, secondary to
vasodilatation (Abbas & Litchman 2003, Cruce &
Lewis 2004). Sera incorrectly purified, or with
excessive total protein load, can contribute to the
development of this reaction. The Razi institute
Zare Mirakabadi / Archives of Razi Institute, Vol. 68, No. 2, December (2013) 91-99
antivenom appeared to have some impurities;
especially below 30 kDa. However an ELISA assay
showed that Razi institute polyvalent antivenin has a
high affinity to H. lepturus venom, suggesting that the
antivenom has specificity for detection and inhibition
of the enzymatic activities of this venom. (Ramin et al
2010).
Conclusion
Based on information provided in this review article
it can be concluded that the venom of scorpion H.
lepturus is mainly cytotoxic in nature causing various
tissue damage in stung patients. The specific polyvalent
antivenom is capable of neutralizing the venom if it is
injected at early time. Intramuscular injection of
specific antivenom is useful before appearance of any
systemic signs and symptoms in patients. However
since the cytotoxic effect of venom is proved to be
irreversible by antivenom if once it occurs, it is
recommended to inject the antivenom by i.v rout if any
systemic signs and symptoms are observed in stung
patients.
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